The National Psoriasis Foundation estimates that there are more than six million Americans afflicted with psoriasis which is a chronic skin disorder. It is not contagious but its etiology is unknown. Most patients with psoriasis have several lesions confined to knees, elbows and scalp. Severe psoriasis affects larger areas such as the back, chest and legs and, not infrequently, the entire body. There are various types of psoriasis and thus there are a number of effective treatments or combinations, but not one that is specific or curative.
The therapeutic armamentariun used to combat the symptoms of psoriasis, available both by prescription and over the counter, include corticosteroids, coal tar, bath solutions, including salts from the dead sea, retinoids, vitamin D3, occlusion therapy, cyclosporine and methotrexate to name a few. Psoralens have been used with ultraviolet A radiation, despite its known carcinogenic properties, much like that caused by sun damage. Ultraviolet B radiation has also been used successfully in some cases.
Psoriasis is considered a hyperproliferative condition of the skin's epithelial cells. This dermatologic condition also includes seborrhoeic keratosis, eczema, warts and dandruff. Psoriasis may be a familial disease for which Bowcock and colleagues have disclosed a method for screening for psoriasis genetic susceptibility in U.S. Pat. No. 5,811,233 dated Sep. 22, 1998. Psoriasis, representing an uncontrolled proliferation of cells, has been variously treated with antiproliferative compounds such as retinoids directed at inhibiting these activities. In its normal state, TGF-Beta secretion has an inhibitory effect on epithelial cell proliferation. Piazza and Mazur disclosed the use of lysophosphatidic acid for treating hyperproliferative conditions in U.S. Pat. No. 5,565,439 issued Nov. 4, 1994. They claim that lysophosphatidic acid mimics the retinoids in their antiproliferative and TGF-Beta secretory properties. Their topical compositions included a variety of other agents with purported or hypothesized genetic properties influencing these hyperproliferative cutaneous maladies.
Various studies have shown increased enzyme activity in polymorphonuclear (PMN) leucocytes in the circulation of patients with psoriasis. Open and co-workers (Clin. Chine. ACTA 264:49, 1997) in Turkey correlated elastase levels in PMN leucocytes to disease activity. The PMN elastase levels were six-fold higher in psoriatic patients with active disease compared to controls, but only two-fold higher during quiescent stages of psoriasis. Not only is the elastase a sensitive marker of disease activity, it is also reflective of a concomitant inflammatory reaction which gives rise to free radical species. Elastase levels in PMNs also correlated with the total white blood cell (PMN) count and the levels of another reflector of inflammation, alpha-1-antitrypsin.
Psoriasis is characterized by hyper-proliferation and incomplete differentiation of epidermal keratinocytes. Psoralen plus ultraviolet A radiation (PUVA) represents one form of therapy, albeit there exists an increased risk of photocarcinogenesis with this treatment. Like the increased risk of cutaneous carcinomas and melanoma from UV radiation, oxygen and other free radical species may be pathogenetic of these neoplasias. PUVA leads to chromosome breakage through the formation of transferable clastogenic factors, whose genesis may be inhibited by the enzyme superoxide dismutase. Elastogenic factors have been detected in patients with psoriasis and with other illnesses associated with oxidative stress, where the free radical superoxide is produced both by phagocytes in the so-called "respiratory burst reaction" and from the process of lipid peroxidation. These elastogenic factors are present in the blood of psoriatic patients and are markedly increased during PUVA therapy. Thus, it is hypothesized by the present invention that the oxidative stress in psoriasis and especially during PUVA treatment may be ameliorated and the risk of photocarcinogenesis decreased by administration both of oral and topical antioxidants.
Psoralens, which are known to be mutagenic and carcinogenic, are components contained in many cosmetic preparations as aids to skin care. These photosensitizers may promote further skin reactions to ultraviolet radiation and result in permanent skin damage, cutaneous aging and malignancies even in patients with psoriasis.
Patients with psoriasis are often treated with oral methoxsalen (psoralens) and ultraviolet A radiation. This photochemotherapy, albeit effective, increases the risk of developing squamous cell skin cancer. Recent articles have also revealed an increased risk for malignant melanoma, especially among patients who receive over 250 treatments after 15 years since initiation. As noted hereinafter, the synergistic antioxidant complex of the present invention may be applied topically prior to and after UVA therapy to neutralize the free radicals so generated and thereby reduce the risk of development of cutaneous malignancies including melanomas in these patients.
Various novel therapies for psoriasis have recently been disclosed, albeit none address the issue of inflammation and free radicals ameliorated by the synergistic antioxidant complex of the present patent application. Quarles in U.S. Pat. No. 5,776,920 dated Jul. 7, 1998, teaches a preparation of salicylic acid, lactic acid, and urea in a moisturizing medium useful as topicals for psoriatic lesions applied once daily for four days. Braiman, using his own psoriasis affected skin, teaches the use of isomers of retinoic acid, namely II-cis-retinoic acid, as a therapeutic agent in U.S. Pat. No. 5,719,195 dated Feb. 17, 1998. Braiman teaches synthesis of neotretinoin as well as a way to irradiate a gel with retinoic acid to create this therapeutic isomer. Winkler and co-workers in U.S. Pat. No. 5,648,373 dated Jul. 15, 1997 teach the use of enzyme inhibitors to block the production of inflammatory mediators (the arachidonic acid cascade). These inhibitory compounds together with co-enzyme A-independent transacylase are purportedly useful in a variety of allergic and inflammatory disorders. Furthermore, the use of omeprazole in the therapy of these skin maladies is disclosed by Hasselkuss in U.S. Pat. No. 5,714,505 dated Feb. 3, 1998. U.S. Pat. No. 5,565,542 dated Oct. 15, 1996 by Eitan and collaborators teach the use of xanthine derivatives, namely, pentoxifylline, propentofylline and torbarylline, as topicals for psoriasis and atopic dermatitis. Medford teaches in U.S. Pat. No. 5,783,596 dated Jul. 21, 1998 the use of dithiolarxy-lates, especially dithiocarbamates as therapies for inflammatory diseases by blocking the induced expression of the endothelial cell surface adhesion molecule VCAM-1 and is thus also of value in treating atherosclerosis and related complications.
Psoralens and UVA bath therapy reportedly benefited the skin of eight of ten patients with psoriasis. Vallat and co-workers at the Rockefeller University (J EXPT MED 180:283, 1994) showed that PUVA bath therapy suppressed both immunological responses and epidermal activation in psoriasis by 70%. The pathologic increase of insulin-like growth factor receptors was reduced as was the increase in keratinocyte proteins at an abnormal site. They concluded this treatment reverses epidermal and lymphocytic activation and renders a more sustained remission in psoriasis.
It has been shown that patients with moderate or severe psoriasis have low blood selenium levels. Corrocher and co-workers (Clin. Chim. ACTA 179:121,1989) not only noted low serum selenium levels in patients with psoriasis but there was also a concomitant increase in the production of malondialdehyde, a reflector of free radical damage in the body. Harvima and collaborators in Finland, (ACTA Derm Venerol 73:88, 1993) supplemented such psoriasis patients with oral selenomethionine, although by this route neither skin selenium levels nor the clinical condition were affected. There was a distinct increase in the numbers of CD4-T lymphocytes which are able to modulate local immunologic mechanisms.
Burke and colleagues (Photoderm, Photoimmuno 9:52, 1992) have demonstrated in both human subjects and experimental animals that topical selenomethionine reduces the degree of UV irradiated damage to the skin. In the murine species, topical selenium also inhibited skin carcinogenesis. It is proposed by the present invention that free radical species are implicated in inducing these skin pathologies, thus, selenomethionine administered topically with its synergistic antioxidant partners will benefit patients with psoriasis, particularly those undergoing PUVA treatments, as preventive of skin cancers and reparative of skin damage.
Bruzzese et al. in U.S. Pat. No. 5,472,705 (Dec. 5, 1995) disclosed topical compositions of Omega 3 polyunsaturated acids for therapy of morbid affections like psoriasis. They included an alkyl ester of a triethylcitrate and a phenolic antioxidant. More recently, Jacob disclosed the use of ingredients of a latex extracted from the leaves of the Wrightia tinctoria R Br plant plus urea and polyethylene glycol as an herbal medication for psoriasis in U.S. Pat. No. 5,858,372, dated Jan. 12, 1999, which is herein incorporated by reference.
Cavazza et al. in U.S. Pat. No. 6,627,212 (May 12, 1997) which is herein also incorporated by reference, disclosed the use of esters of I-carnitine combined with hydroxy acids to treat dermatoses. A list of preferred hydroxy acids was further disclosed. The dermatoses listed as suitable for therapy with I-carnitine and these acids included ichthyosis, psoriasis and those induced by defective keratinization such as dandruff, acne, and palmar and plantar hyperkeratosis. Although the inventors recite these combinations, alone, or with accepted therapies for these dermatoses, no scientific evidence is given as to mechanisms by which they exert their pharmacologic effects.
The epidermis in psoriatic skin, much like skin which has sustained a significant burn, has increased levels of the enzyme xanthine oxidase. This enzyme, like phagocytic cells and skin fibroblasts, is capable of generating free oxygen radicals. In an experimental mouse model, an inflammation induced by a specific chemical (TAP) was associated with high xanthine oxidase activity and concomitant epidermal cell hyperplasia. This experimental finding is similar to what occurs in psoriatic skin, where there is an observed five-fold increase in xanthine oxidase and cellular hyperproliferation. It is not known if this increase in xanthine oxidase is responsible for epidermal hyperplasia in psoriasis.
A relationship has been established between the lesions of seborrhoeic dermatitis and pityrosporum yeast species. Although the numbers of P. ovale organisms do not correlate with disease activity, these may relate to the hosts' abnormal immune responses, such as occurs in patients with AIDS for these patients are known to have high frequencies of both seborrhoeic dermatitis and psoriasis. Patients with AIDS tend to have low blood counts of CD4-T lymphocytes. Their disease activity and their survival rate, however, depends not just on CD4-T lymphocyte cell counts but more on their HIV viral load and on the cells' content of glutathione (GSH). The lower the GSH level in the T-lymphocyte, the greater the replication of the HIV virus and the poorer is the prognosis for that patient. HIV positive subjects may also have low levels of selenium and of other antioxidants thus impairing immunologic protection. Selenium restores CD4-T lymphocyte function to deal effectively with pityrosporum yeasts. While inflammation induced by these yeasts in the scalp is prevalent, this creates free radical species and requires the cells' antioxidant defense mechanisms to help improve the severity of the seborrhoeic dermatitis.
Another mechanism for inflammation is due to the content of lipase by pityrosporum species which can generate free fatty acids. These too create free radicals requiring the antioxidant response to neutralize and nullify their toxic effects on the scalp. Additional therapies for seborrhoeic dermatitis include antimycotic agents and drugs that reduce sebum excretion. Shampoos with zinc pyrithione are used as adjuncts to therapy of seborrhoeic dermatitis. The mechanism is from zinc's healing and antimicrobial properties.
Zinc pyrithione shampoos may be further enhanced by the group of synergistic antioxidants of the present application. The glutathione cycle would neutralize free radicals and thereby reduce the inflammatory reaction and also decrease the levels of the deleterious enzyme elastase. It is hypothesized that the addition of topical GSH with selenomethionine or other synergistic partners will improve local immunologic function and be therapeutically beneficial.
Patients with seborrhoeic dermatitis have been shown to have low plasma levels of vitamin E, selenium, erythrocyte glutathione peroxidase, wherein selenium is a co-factor, and of polyunsaturated fatty acids. These low nutrient blood levels were recorded whether these patients with seborrhoeic dermatitis were HIV positive or HIV negative. These investigators ascribed these deficiencies to the pathogenesis of seborrhoeic dermatitis. They then patented a reparative shampoo composition as adjuvant therapy consisting of selenium, methionine and vitamin E as a protective response to scalp damage caused by the process of lipid peroxidation in these cases. See Ippolito, U.S. Pat. No. 5,290,809. Another composition of selenium as the sulfide is a well known component in anti-dandruff shampoos (Rappaport, M J., Int. Med. Res. 9:152, 1981). Bergbrant (Curr. Topics Med. Myco. 6:95, 1995) stresses that the numbers of the pathogenetic pityrosporum yeasts in seborrhoeic dermatitis patients is not related to their numbers in the scalps of affected individuals. The reference describes these micro-organisms as etiologic due to altered cell-mediated immunity, akin to the low levels of CD4-T lymphocytes which are also glutathione depleted in patients with AIDS. The Pityrosporum ovale species, which is rich in lipase content, causes an inflammatory response in the scalp. There is then an increase in the release of the enzyme elastase from leukocytes which further generates free radicals and induces tissue damage. Impaired immune function, the inflammatory leukocytic reaction, and P. ovale lipase activity need be reduced to ameliorate seborrhoeic dermatitis. The antioxidant complex of the present invention is prime as an adjunct of therapy.
Drugs that reduce sebum and antimycotic therapies, including the anti-infective zinc pyrithione, require adjuvant therapy as from locally administered antioxidants, including glutathione, cysteine, superoxide dismutase and selenium. The antioxidants of the present invention neutralize the free radicals and ameliorate the inflammatory reaction which help to improve immune function although the frequency of seborrhea reported in patients with AIDS suggests that an alternate etiology may also be at play. Passi and Ippolito in Italy have reported deficiencies in blood levels of vitamin E, polyunsaturated fatty acids and erythrocyte glutathione peroxidase in patients with seborrhoeic dermatitis. These were at the same levels with HIV positive and negative patients compared to suitable controls. Further, Passi and Ippolito disclosed methods for adjuvant treatment of seborrhoeic dermatitis in U.S. Pat. No. 5,290,809 (issued Mar. 1, 1994). The disclosed composition contains pharmaceutical quantities of amino acid methionine, tocopherol and selenium.
Zinc pyrithione shampoos were evaluated in 32 subjects who suffered from dandruff, using half of the head for the test material and the other for a placebo (vehicle shampoo minus the zinc compound). Dandruff gradings and scalp biopsies were done. There was a progressive reduction in dandruff in the side of the head treated with the zinc shampoo. (Marks, R. et al. BRJ Derm. 1 12:415, 1985).
U.S. Pat. No. 4,503,047, showed the value of sulphur amino acids, like cysteine and methionine, in compositions for stimulating keratin formation in hair bulbs employing horseradish and mustard seed extracts. This invention related to hair growth stimulating compositions.
In other studies in human subjects, topical selenomethionine was investigated for its ability to reduce the degree of acute damage to the skin by sunburn as induced experimentally by ultraviolet irradiation. Eight women were treated for two weeks with a lotion vehicle and then with three concentrations of selenomethionine (0.002%, 0.02% and 0.05%). The researchers found that topical selenomethione was effective in protecting against acute UV damage to the skin, as measured by the minimal erythema dose, using a multiport solar ultraviolet simulator. Plasma levels of selenium in these volunteers remained unchanged, suggesting the protective effect of the selenomethionine was locally at the skin. The effects demonstrated by the topically applied selenomethionine in human volunteers suggests that the protection to ultraviolet irradiation is not simply a sunscreen effect. The selenomethionine is absorbed percutaneously and acts locally as a free radical scavenger.
Antioxidants, generally, have been found to inhibit all stages of carcinogenesis whereas some antioxidants are more specific and thus more effective against tumor imitation, or tumor promotion. Glutathione and selenium have been shown to play prime roles in protection of carcinogenesis, the latter particular in skin tumors, when selenium is applied locally but also in preventing other cancers, when selenium is taken orally and thereby replenishing selenium body stores. Likewise, glutathione, the most abundant tissue thiol and antioxidant, inhibits carcinogenesis. When glutathione concentration in cells is suppressed by chemicals so that glutathione levels are significantly lowered, chemical carcinogenesis is enhanced and progression of tumor numbers and tumor size increases. Thus, these studies show the value of glutathione in prevention of tumor formation, making it the ideal antioxidant ingredient along with other synergistically acting antioxidants included in these dermatologic preparations.
The role of intracellular GSH in irradiated cancer cells has been investigated. Reducing the intracellular levels of GSH in tumor cells increases their sensitivity to irradiation or oxidant damage mediated by activated neutrophils or macrophages. Inhibition of GSH synthesis also augments lysis of murine tumor cells by sulfhydryl-reactive anti-neoplastics. Thus, neoplastic cells depleted of their endogenous protective antioxidant, GSH, are more sensitive to radiation damage. Conversely, other studies have shown that increases in intracellular GSH are beneficial. Endothelial cells treated with an L-cysteine delivery agent not only enhance endothelial cell GSH concentration, but also protected these cells in an inverse, linear relationship from damage by endogenous hydrogen peroxide. This preventive role of GSH is of value in treating skin where the psoralens and UVA are being delivered.
Cysteine, one of the three amino acid constituents of GSH, has the "SH" group and thus, on its own, this thiol also possesses antioxidant properties. Therefore, it has been utilized as such or as a cysteine derivative, like n-acetyl-I-cysteine, for dermatologic, oral and prenatal preparations. It is the treatment of choice in hepatic toxicity by acetaminophen (Tylenol). Hildebrand, in U.S. Pat. No. 5,296,500 (Mar. 22, 1994), which is herein incorporated by reference discloses the use of N-acetyl-L-cysteine for regulating wrinkling of the skin, a sign of photoaging, and atrophy of the skin, also a sign of chronologic aging. The teaching is also both for prevention and treatment of sunburn and increasing the speed of skin pigmentation. Hildebrand also teaches its use in pharmacologically acceptable salts, including zinc compounds. His list of zinc salts does not list zinc pyrithione nor does this patent deal with therapy of dandruff, psoriasis, acne or other dermatoses.
Sharpe et al. in U.S. Pat. No. 5,637,616 (Jun. 10, 1997), which is herein incorporated by reference, taught the use of topical preparations with effective amounts of N-acetyl-L-cysteine in diseases mediated by proteases. These maladies include pemphigus, pemphigoid varieties and lichen planus.
However, none of the art considered above, taken either simply or in combination teach the use of reduced glutathione and a selenium source such as selenoamino acid for treating psoriasis, seborrheic dermatitis and related conditions.